Hospital Infection Control

Yeast/molds – Aspergillus

What are the key principles of preventing yeast/molds – Aspergillus?

The key principles regarding the prevention of invasive aspergillosis (IA) involve prevention of exposure to spores and prevention of disease in patients at risk.

Successful implementation of preventive efforts rely on education of health care personnel as to the importance of prevention and their role in implementing the necessary procedures, risk stratification of the patient population to ensure appropriate application of preventive measures, and active surveillance for cases of healthcare-associated IA as an additional means of recognizing the need for, and targeting specific populations for intervention.

Education of staff and infection surveillance

Education

It is very important to educate healthcare personnel (clinical, infection control [IC], cleaning staff, administrators, and individuals involved in construction/renovation) and patients in order to successfully implement effective IC preventive measures.

Healthcare workers should be educated on the risk of IA in specific patient groups and in the IC measures to decrease its occurrence.

Personnel involved in all stages of construction/renovation should be educated on the preventive measures that must be implemented during construction/renovation activities and the importance of compliance at every level (project managers, contractors, design teams, and construction workers).

Supervisors of cleaning staff/contract cleaners should be educated on the principles of Aspergillus spore contamination of the environment and the cleaning measures to prevent environmental contamination. This information should be transmitted to cleaning personnel in order to aid in compliance.

At-risk patients (see below) and their relatives should be informed of the risks of IA and the necessity for prevention.

Classification of patient risk groups

Group 1 – No evidence of risk:

Staff members, service providers, and contractors.

All patients not listed in Groups 2-4 below.

Group 2 – Increased risk:

Patients on prolonged courses of high dose steroids particularly those hospitalized for prolonged periods.

Prolonged neutropenia for greater than 14 days following chemotherapy or immunosuppressive therapy.

Aplastic anemia patients.

Surveillance

Implicit in the successful prevention of IA is the performance of active surveillance by the IC team.

Maintain a high index of suspicion for healthcare-associated IA in severely immunocompromised patients (i.e., patients with severe prolonged neutropenia [ANC <500/mm3 for 2 weeks or <100/mm3 for 1 week], most notably hematopoietic stem cell transplant [HSCT] recipients, and including recipients of SOT or patients with hematologic malignancies who are receiving chemotherapy, when they are neutropenic) and persons receiving prolonged high dose steroids (risk groups 2-4).

Maintain surveillance for cases of IA by establishing a system by which IC personnel are promptly informed when Aspergillus spp.are isolated from cultures of specimens from patients’ respiratory tracts and by periodically reviewing the hospitals microbiologic, histopathologic, and post mortem data.

Aggressively pursue the diagnosis in cases of suspected IA with tissue biopsies and cultures as feasible.

Surveillance cultures:

Do not perform routine, periodic cultures of the nasopharynx of asymptomatic patients at risk.

Do not perform routine, periodic cultures of equipment or devices used for respiratory therapy, pulmonary function testing, or delivery of inhalational anesthesia in the HSCT unit, nor of dust in rooms of HSCT patients.

No recommendation can be made about routine microbiological air sampling before, during, or after facility construction or renovation, or before or during occupancy of areas housing immunocompromised patients due to the fact that it has been impossible to relate a specific number of airborne spores to a quantifiable infection risk among patients of any risk group.

In facilities with preventive/protective environments (PEs), perform surveillance of the ventilation status of these areas either by continuous monitoring or periodic analysis of the following parameters: room air exchanges, pressure relations, and filtration efficacy, to ensure that appropriate levels are maintained.

Prevention of transmission of Aspergillus spores

All guidelines for the prevention of healthcare-associated IA stress the necessity of housing severely immunocompromised patients in a PE and include detailed recommendations on preventing IA with a water source, environmental source, or transmission by the airborne route.

Planning new specialized-care units for high-risk patients

PE for allogeneic HSCT recipients:

When constructing new specialized-care units with PE for HSCT recipients, ensure that patient rooms have adequate capacity to minimize accumulation of fungal spores via:

HEPA filtration of incoming air.

Directed room airflow.

Positive air pressure in patient’s room in relation to the corridor.

Well-sealed room.

High (≥12) air changes per hour.

An Infection Control Risk Assessment (ICRA) should be created by IC and maintenance personnel to develop protocols for the protection of HSCT patients at all times from bursts of mold spores that might occur when air-handling systems are restarted after routine maintenance.

Do not use laminar airflow (LAF) routinely in PE.

Units for autologous HSCT and SOT recipients:

No recommendation can be made for routinely placing immunosuppressed patients other than allogeneic HSCT recipients in PE.

Wet-dust horizontal surfaces daily using cloth that has been moistened with an EPA-registered hospital disinfectant.

Avoid dusting methods that disperse dust (e.g., feather dusting).

Keep vacuums in good repair and equip them with HEPA filters for use in areas with patients at high risk.

Do not use carpeting in hallways and rooms and avoid upholstered furniture or furnishings in rooms occupied by severely immunocompromised patients.

Minimize the length of time that immunocompromised patients in PEs are outside their rooms for diagnostic procedures and other activities:

Instruct severely immunocompromised patients to wear a high-efficiency respiratory-protection device (e.g., a N95 respirator) when they leave the PE during periods when construction, renovation, or other dust-generating activities are ongoing in and around the healthcare facility.

No recommendation can be made about the specific type of respiratory-protection device for use by a severely immunocompromised patient who leaves the PE during periods when there is no construction, renovation, or other dust-generating activities in progress in or around the healthcare facility.

Systematically review and co-ordinate IC strategies with personnel in charge of the facility’s engineering, maintenance, central supply, and distribution and catering services.

When planning construction, demolition, and renovation activities in and around the facility, assess whether patients at high-risk for IA are likely to be exposed to high ambient air spore counts of Aspergillus spp. from the involved areas, and if so, develop a plan to prevent such exposures:

Construct barriers to prevent dust from construction areas from entering patient-care areas; ensure that barriers are impermeable to fungal spores and in compliance with local fire codes.

Block and seal off return air vents if rigid barriers are used for containment.

Implement dust control measures on surfaces and by directing pedestrian traffic away from work zones.

Relocate patients who have been located in rooms adjacent to work zones, depending upon their immune status, the scope of the project, the potential for generation of dust or water aerosols, and the methods used to control those aerosols.

Ensure proper operation of the air-handling system in the affected area after erection of barriers and before the room or area is set to negative pressure.

Create and maintain negative air pressure in work zones adjacent to patient-care areas and ensure that required engineering controls are maintained.

Monitor negative airflow inside rigid barriers.

Monitor barriers and ensure the integrity of the construction barriers; repair all gaps and breaks in the barriers.

Seal windows in work zones if practical; use window chutes for disposal of debris as needed, but ensure maintenance of the negative pressure differential.

Direct pedestrian traffic that comes from work zones away from patient-care areas to minimize dispersion of dust.

Clean work zones daily by wet-wiping tools and carts, placing mats with tacky surfaces inside the entrance and covering debris before removal.

In patient-care areas, for major repairs that disrupt the space above the false ceiling, use plastic barriers to contain dust and use a negative pressure system within the enclosure and either pass air through a HEPA filter or exhaust directly to the outside.

Upon completion of the project decontaminate the work zone and install barrier curtains to contain dust and debris before removing rigid barriers.

Flush the water system to clear sediment from pipes to minimize microorganism proliferation.

Assess whether the infection is healthcare-related or community-onset.

Obtain and use the following information to help in the investigation:

Background rate of disease at the facility.

Presence of concurrent or recent cases, as determined by a review of microbiologic, histopathologic, and post mortem records.

Length of stay (LOS) in the facility prior to onset of IA.

Patient’s stay at, visit to, or transfer from other healthcare facilities or other locations within the facility.

Period the patient was exposed outside the facility after the onset of immunosuppression and before the onset of IA.

Determine if any ventilation deficiency exists in PEs and implement corrective measures as needed.

If no evidence exists that the patient’s aspergillosis is facility-related, continue routine procedures to prevent healthcare-associated IA.

If evidence of possible facility-related IA exists, conduct an epidemiologic investigation and an environmental assessment to determine and eliminate the source of Aspergillus:

Construct an outbreak curve.

Line listing of all infected patients with a review of pertinent clinical data.

Evaluation of the air handling system including flow rates, pressure differentials, and potentially contaminated filters or ducts.

Assessment of any water damage of adjacent walls, ceilings, or floors.

Possible common source exposure.

Volumetric air sampling (no settle plates) and environmental cultures, including water sources, may suggest a possible source. Molecular typing of patient and environmental isolates may aid in linking a specific environmental source to patient isolates.

If either an environmental source or an engineering problem with filtration or pressure differentials is identified, promptly perform corrective measures to eliminate the source and route of entry.

Use an EPA-registered antifungal biocide (e.g., copper-8-quinolinolate) for decontamination of structural materials.

If an environmental source of airborne fungi is not identified, review IC measures, including engineering controls, to identify potential areas for correction or improvement.

Prevention of disease

Patients at risk for IA should be considered for prophylaxis with mold-active drugs during periods at risk:

Posaconazole

Voriconazole

Itraconazole oral solution

Micafungin, caspofungin

Aerosolized liposomal amphotericin B

No recommendation can be made for the use of growth factors (e.g., GM-CSF, G-CSF) for prophylaxis against IA.

Patients with prior IA should receive secondary prophylaxis with a mold-active agent. Voriconazole has been shown to have benefit for this indication.

What are the key conclusions for available clinical trials and meta-analyses that inform control of yeast/molds – Aspergillus?

The current guidelines are largely derived from an assessment of outbreak evaluations and remediation. There are few controlled trials demonstrating the efficacy or effectiveness of recommended methods for preventing nosocomial IA.

Protective isolation and high-efficiency particulate air filtration

Convincing results from comparative clinical studies supporting a benefit from the routine use of HEPA filters are scarce. Given the lack of randomized clinical comparisons, evidence supporting the benefit of protective isolation and HEPA filtration mainly comes from retrospective cohort analyses or from meta-analyses of pooled published data on HSCT recipients.

Passweg et al. reported that among the more than 5500 patients documented in the International Bone Marrow Transplant Registry undergoing allogeneic HSCT, isolation and HEPA filtration were associated with superior overall survival after sibling as well as unrelated donor transplants.

A meta-analysis by Eckmanns et al. showed only a vague trend in favor of isolation, but no significant survival benefit.

Use of well-fitting face masks while outside protective environments

A prospective randomized study on the use of well-fitting FFP2 masks in patients undergoing intensive chemotherapy for acute myeloid leukemia or allogeneic HSCT failed to show any benefit with respect to the incidence of invasive fungal infection (IFI).

In contrast to clinical practice and current expert guidelines, the routine use of well-fitting face masks does not appear to be beneficial for preventing IA outside of specific settings with an excess burden in room air of fungal spore-loaded dust during hospital construction.

Antifungal chemoprophylaxis

A meta-analysis of clinical trials on antifungal prophylaxis among more than 7000 severely neutropenic chemotherapy recipients conducted before 2000, as well as a more recent evidence-based review, demonstrated a significant reduction in the incidence of fungal infections, as well as a reduction of fungal infection-related mortality by antifungal prophylaxis. Mortality due to IA was not reduced by fluconazole prophylaxis, but rather increased with this regimen.

Among 304 allogeneic HSCT recipients, a superior protection from invasive mold infections by itraconazole versus fluconazole was noted among patients who were able to tolerate long-term oral administration of itraconazole.

Three prospective randomized clinical trials comparing the efficacy of new mold-active azole antifungal agents (posaconazole and voriconazole) for prophylaxis of IFIs among severely neutropenic patients and allogeneic HSCT recipients with moderate-to-severe GVHD were conducted.

Patients with prior IA should receive secondary prophylaxis with a mold-active agent.

Voriconazole has been shown to have benefit for this indication.

Growth factors for prophylaxis

No recommendation can be made for the use of growth factors for prophylaxis.

A meta-analysis showed that the use of growth factors did not reduce the attack rate of IFI.

What are the consequences of ignoring key concepts related to control of yeast/molds – Aspergillus?

The consequences of ignoring key concepts related to the control of IA (prevention of exposure and prevention of disease) include increased numbers of infections with associated high rates of morbidity and mortality.

IA has been reported in 2-26% of HSCT recipients and in 1-15% of SOT recipients. Historically the mortality rate has ranged from 74-92%. An estimated 9.3-16.9% of all deaths in transplant recipients in the first year post-transplant are attributed to IA.

Vonberg and Gastmeier have reviewed 53 outbreaks of IA involving 458 patients between 1967 and 2005 and report an overall mortality of 55%. The mortality by patient type was as follows: hematologic malignancy 58%, SOT 56%, other immunosuppressed patients 52%, and non-immunosuppressed patients 39%.

What other information supports the key conclusions of studies of yeast/molds – Aspergillus e.g., case-control studies and case series?

The vast majority of existing guidelines focus on minimizing exposure of high-risk patients to fungal spores and are largely based on expert consensus and retrospective studies of outbreaks of IA. The epidemiology and mechanisms of outbreaks of IA, as well as the interventions undertaken to control them, provides the foundation for the current IC guidelines. The latter fact may be considered a limitation to the guidelines as they may not serve to prevent sporadic IA.

The vast majority of the data supporting environmental controls for the prevention of IA come from outbreaks of infection linked to construction, renovation, and/or demolition. The key to eliminating IA is first to minimize the dust generated during construction activity and second to prevent dust infiltration into patient care areas.

In a review of 43 outbreaks of IA, Vonberg and Gastmeier observed that 49% were associated with construction.

Loo et al. described an outbreak of IA in which the following environmental control measures were used:

Copper-8-quinolinolate formulation was applied to walls, doors, frames, baseboards, exterior surfaces of radiators, vents in the rooms, and above the false ceilings of the adjacent hallway to decontaminate the area.

Patients were moved to a different area of the hospital during the implementation of these measures.

The authors concluded that the environmental control strategy implemented played an important role in controlling the outbreak of IA. Unfortunately, since multiple interventions were instituted simultaneously to eliminate the outbreak, the efficacy of a single measure (e.g., decontamination with copper-8-quinolinolate) is impossible to assess.

Thio et al. described an epidemiological investigation and environmental assessment following an increase in incidence of IA in patients with leukemia and HSCT recipients.

They suggested that excess cases of IA were linked to spores entering the oncology unit from the physically adjacent building because the air pressure in the oncology unit was negative with respect to the adjacent building. The combination of patient use of N95 masks when leaving their HEPA filtered rooms and wet mopping to reduce aerosols was associated with reduction in cases of IA.

There are no recommendations regarding the pressure differential between an HSCT center and adjoining buildings, although a pressure differential for positive pressures of greater than 2.5 pascals between any PE and adjacent hallways or anterooms has been proposed.

Arnow et al. described an increased incidence of IA in immunocompromised patients that coincided with hospital construction and poor maintenance of air filters.

Taken together outbreak studies support the following recommendations:

Controlling IA requires a multi-disciplinary team composed of facility and maintenance personnel with a good understanding of building airflow, heating, ventilation, and air conditioning systems and air filter maintenance. It should also include IC personnel to ensure that protective measures are followed and to conduct active surveillance for cases of IA. Housekeeping staffs require education regarding proper cleaning and minimizing dust dispersal, and environmental safety personnel should be included as they are responsible for overall building safety measures.

There is a need for developing air sampling and pressure testing standards to determine the effectiveness of containment efforts during construction.

Some experts suggest measuring fungal spore concentrations in periods of construction or during outbreaks. However, this approach is limited by the lack of standardized methods for air sampling and quantitation of fungi and lack of defined reference ranges for what constitutes unacceptably high levels of fungal spore concentrations in air samples. Despite the fact that the cause-and-effect relationship between airborne Aspergillus spore level and IA is difficult to quantify, it is clear that decreasing the spore level in the air is instrumental to reducing the risk of nosocomial IA.

Thus, it has been suggested that if the total fungal count exceeds 1.0 CFU/m3 on several occasions, the air systems or procedural practice in patient care areas requires intensive evaluation.

Plants, soil, and gardening

Exposure to plants and flowers has not been shown to conclusively cause IA in HSCT recipients. Regardless, most experts recommend that plants and dried or fresh flowers should not be allowed in hospital rooms during conditioning or after HSCT because Aspergillus spp. have been isolated from these sources.

Recipients and candidates for HSCT should avoid contact with soil-based materials.

Food

There are several studies demonstrating that Aspergillus spp. and other molds colonize plants and other food products.

Several centers use “low microbial diets” to limit exposure to bacteria and fungi in high-risk patients. Criteria for “low microbial diets” differ among centers and no standardized definition exists.

A common sense approach involves avoiding fresh fruits and vegetables that cannot be effectively washed.

Water

Aspergillus and other opportunistic molds (Fusarium spp.) are present in water and water-related surfaces of hospitals caring for cancer patients, and molecular studies have suggested the potential relatedness of environmental and clinical strains.

Hospital water should be considered a potential source for nosocomial IA.

Although some investigators believe it to be necessary to decrease patient exposure to hospital water during periods of severe immunosuppression, current data are insufficient to support the formulation of definitive recommendations.

Standing water, water-damaged ceilings, floors and walls, damp basements, and other moist indoor environments can be colonized with high levels of molds and therefore constitute a potential threat to highly immunocompromised patients.

Water leaks should be cleaned up and repaired as soon as possible, but within 72 hours to prevent mold proliferation.

If cleanup and repair are delayed by greater than 72 hours after a water leak, the involved materials should be assumed to contain fungi and be discarded (preferred) or cleaned.

Evidence supporting the benefits of protective isolation and high-efficiency particulate air filtration

Numerous reports in the literature indicate a significant benefit from isolation procedures and room-air filtration in hospitals affected by heavy fungal contamination of air caused by hospital renovation or by outbreaks of IA. However, results from comparative clinical studies are rare.

Protective isolation

Following extensive clinical use of PEs in the 1970s, a critical review found that a significant survival benefit to leukemia patients treated in isolation wards compared to those in open wards treated with oral antimicrobial prophylaxis had not been observed.

Two small comparative studies showed contrasting results with no benefit and a significant benefit.

Anderson et al. reported an outbreak of nosocomial IA on a pediatric oncology ward that was linked to a poorly sealed waste disposal unit and the ward vacuum cleaner. The outbreak was terminated coincident with the sealing of the disposal unit and replacement of the vacuum cleaner with a high-efficiency unit.

Although HEPA filters do not offer complete protection from IA, several retrospective studies suggest that it significantly reduces the risk of IA. Some published evidence suggests that HEPA filtration also can significantly reduce the airborne concentrations and/or infection rates for a wide range of aerosolized pathogens including Staphylococcus aureus, Pseudomonas, mycobacteria and some viruses.

In a retrospective cohort study, Hahn et al. found that the use of HEPA filtration was effective in controlling an outbreak of IA linked to contaminated insulation. Following the institution of HEPA filters the incidence of IA decreased from 10 infections in 55 patients over a 6-month period to 2 cases over a 2-year period.

Oren et al. observed a dramatic increase of IA (up to 50%) among acute leukemia patients during a phase of extensive hospital construction, which was completely reversed after opening a newly built HEPA-filtered ward. Patients treated thereafter in a regular ward had an IA rate of 20-30%, while in the HEPA-filtered ward no IA cases were documented.

Sherertz et al. also noted a significantly lower incidence of IA among patients treated in HEPA-filtered wards compared to those treated in regular wards, for whom no bed on a HEPA-equipped ward was available.

Portable HEPA filters have been used as part of a successful strategy to prevent fungal infections. However, whether they are as effective as central or point-of-use HEPA filters in preventing IA has not been studied.

Laminar airflow rooms contain HEPA-filtered air that moves in a parallel, unidirectional flow (air enters the room from one wall and exits from the opposite wall). Some studies show that laminar airflow may protect patients from IA during hospital construction. However, routine laminar airflow use for all HSCT recipients has not been shown to provide substantial overall survival benefit, and thus is not recommended for newly constructed rooms in HSCT centers.

Precautions in the outpatient setting

Allogeneic HSCT recipients requiring intensive immunosuppression are frequently managed as outpatients where the degree of environmental protection provided by PEs cannot be maintained.

There are a number of consensus-driven, common sense recommendations by the CDC to reduce exposure to mold spores in the outpatient setting.

Avoid sources of mold such as construction sites, areas of standing water, and damp basements.

Family members should vacuum using HEPA-equipped machines and use a wet method for dusting. Patients should leave the room during these activities.

Use common sense in dealing with food: check expiration dates, inspect for mold growth, and discard leftover foods in the refrigerator after 72 hours.

Well water should be filtered or tested by health officials, and fruits and vegetables should be thoroughly washed.

Meticulous hand hygiene is always recommended.

Summary of current controversies.

The current controversies regarding efforts to prevent IA are largely due to incomplete or absent data. They will be listed here as areas where current guidelines offer no recommendations and as additional areas where data is lacking or confusing.

Areas where current guidelines offer no recommendation

These are issues where judgment and common sense are very important and where studies generating new data remain critically important. In most cases the word “routine” is key. That is to say that the precautions may very well be needed in certain instances but not as a “routine”. More guidance is needed here.

Routine microbiological air sampling before, during, or after facility construction or renovation or before or during occupancy of areas housing immunocompromised patients.

Routinely placing a recipient of autologous HSCT or SOT in a PE.

Use of specific types of respiratory protection devices for use by a severely immunocompromised patient who leaves the PE during periods where there is no construction, renovation, or other dust-generating activity in progress in or around the healthcare facility.

Whether or not to allow dried flowers or potted plants in patient-care areas for immunocompromised patients.

Use of growth factors for prophylaxis against IA.

Additional areas where data is lacking or confusing

Relationship between airborne Aspergillus spore counts and risk of IA.

Usefulness of Aspergillus strain typing in outbreak investigation.

Applicability of current guidelines in preventing sporadic IA.

Recommendations on preventing IA in the outpatient setting.

Efficacy of single interventions such as surface decontamination with copper-8-quinolinolate.

Importance of hospital water supply as a source of IA and what are appropriate preventive measures.

Impact of Aspergillus colonization before hospitalization on incubation of IA.

Association between length of hospital stay and IA occurrence.

Use of laminar airflow.

Use of portable versus central HEPA filters.

Application of current guidelines to non-transplanted immunocompromised patients at high risk for IFI.

Which commercially available masks, including N95 respirators, have efficacy in reducing patient exposure to Aspergillus in hospital construction/renovation areas?

Need for chemoprophylaxis to provide additional protection during periods of heavy construction.

What is the role of and impact of yeast/molds – Aspergillus or infections and the need for control relative to infections at other sites or other specific pathogens?

IA is among the most common and deadly infections among allogeneic HSCT and SOT recipients and other groups of highly immunocompromised patients.

Clearly these patients are also at risk for other nosocomial infections such as those due to methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), multi drug-resistant gram-negative rods (MDR-GNR), Candida, Legionella, and an array of viruses.

Given that environmental controls employed to prevent IA are designed to minimize exposure to aerosols, they also provide protection from many bacterial and viral pathogens that may be dispersed by aerosol formation.

Given that any of these potential pathogens may prove lethal when introduced into the compromised host, the use of PEs and antimicrobial prophylaxis is widespread. Effective prophylactic and directed antimicrobial therapy and vaccination strategies are widely available for many bacterial and viral infections, yet are limited for the prevention and treatment of fungal infections.

In contrast to the common bacterial and viral infections, the diagnosis of fungal infections is difficult and the outcome of treatment is dismal. Preventive measures are essential to limit the morbidity and mortality of fungal infections in the immunocompromised host.

Overview of important clinical trials, meta-analyses, case control studies, case series, and individual case reports related to infection control and yeast/molds – Aspergillus.

What national and international guidelines exist related to yeast/molds – Aspergillus?

Guidelines for Design and Construction of Health Care Facilities. 2006.

“Centers for Disease Control and Prevention. Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. Recommendations of CDC, the Infectious Diseases Society of America, and the American Society of Blood and Marrow Transplantation”. MMWR. vol. 49. 2000. pp. 1-126.

“Centers for Disease Control and Prevention. Guidelines for environmental infection control in healthcare facilities (2003)”. Recommendations of CDC and Healthcare Infection Control Practices Advisory Committee (HICPAC).